Clinical, histopathological, and experimental biological investigations have defined the characteristics of human melanocytes as they progress from benign to malignant lesions. Each of the five clinicopathologic steps of progression has been delineated in its relation to others and in its clinical significance. However, the molecular mechanisms of melanoma development and progression are still poorly understood. This program project has three major objectives which are investigated with unique models and tools: 1. Delineate the role of the microenvironment in melanocyte transformation, melanoma progression and host response. Project 1 investigates the microenvironment that controls melanocyte stem cell differentiation. When stem cells are activated to divide and differentiate they are likely highly susceptible to UV-induced DNA damage, which then leads to genetic aberrations (Project 2). The group determines the endogenous and exogenous mechanisms of cells escaping from the normal homeostatic environment in skin and of subsequent transformation to melanoma. Likely, the microenvironment also controls attraction of T cells to the tumor and determines their specificity and biological activity (Project 3). 2. Identify molecular mechanisms of transformation and progression. The group is testing the hypothesis that UV response genes are causatively involved in lentigo maligna melanoma (LMM) development from lentigo maligna, based on epidemiological data and our findings that chromosomal deletions in LMM include the XPG and HUS1 genes that are part of the replication checkpoint and nucleotide excision repair pathways (Project 2). The functional significance of the contribution of the replication checkpoint genes for melanoma development and maintenance is tested in Projects 2 using models of human melanoma development and progression developed in Projects 1 and 3. 3. Develop new targets for melanoma therapy. The group will identify new targets for therapy through genetic, biological, and immunological approaches. Comparative genomic hybridization (CGH) analyses of melanoma lesions (Project 2) will identify chromosomal regions with aberrations. T helper cells from melanoma patients will define new antigens that are immunogenic in patients (Project 3). Immunological approaches to melanoma marker identification have characterized in recent years a variety of proteins that are coded by mutated genes. The biological models developed in projects 1 and 3 will be utilized to select, verify and validate new targets for a growing pipeline of novel strategies for melanoma diagnosis, prognosis, prevention and therapy.